The asymmetric synthesis of γ-fluoroleucine-α-amino acids is a proven technology for the production of potential pharmaceutical compounds that have a wide array of biological uses, including enzyme inhibitors, receptor antagonists and lipophilicity enhancing agents. The use of enzyme mediated dynamic kinetic resolution ring opening of azalactones has been demonstrated as an effective way of introducing stereochemistry in γ-fluoroleucine ethyl ester compounds.
The instant invention describes a novel reaction that includes spontaneous racemization of an azalactone via enol tautomerization. This racemization results in improved yield and ee over other reactions previously described. Additionally, the instant invention is suitable for large scale production. Previously known processes were not economically feasible for large scale production, specifically because of the large amount of enzyme required to run the reactions
The fed batch reactor makes the enzymatic production of fluoroleucine ethyl ester economically feasible for large scale production. An increased temperature over previously known processes, along with a substrate charging strategy, reduces the enzyme to substrate ratio to 1:4. The ester yield is also increased about 5% over previously known processes.
The plug flow column reactor solves the problem of enzyme deactivation by extending enzyme life about 20 fold versus previously known processes. Enzyme deactivation, due to shear in batch systems, is reduced from about 10% per hour to 0.5% per hour. The column process uses a 1:20 ratio of enzyme to substrate and provides for ester product with 90% yield and 86% ee, which is a greater than 20 fold improvement over previously known processes. Also, the column process shows a large cost reduction in the amount of enzyme that is needed.